Compositions of medicinal preparation and hyaluronic acid for treatment of conditions and disease

The present invention provides compositions for the treatment of diseases (e.g., cancer) and conditions utilizing the property of hyaluronic acid and its derivatives for the targeted transport of drug substances to the treated (target) tissue.

Preconditions of the invention

An article by Sandra Blakeley entitled Solid Cores of Tumors Keeping Out Best Drugs, published in 1989. July 8, ed. Globe and Mail, Toronto, Ontario, indicate that more and more researchers believe that, largely because of a misunderstanding of solid-state tumors, researchers are developing anti-cancer drugs that are ineffective for most patients.

As mentioned in that article, according to dr. Cheberman, director of the Pittsburgh Cancer Center, has, over the past decades, been developing drugs, simply injecting into the circulatory system, resulting in a tumor, but researchers are not evaluating how the drug is distributed to the tumor when it reaches it.

The article also states that according to dr. Judah Folkman, a leading researcher in the field of blood poetics at Harvard Medical School, has for many years been considered by doctors to be developing tumors in her circulatory system. This is wrong according to this article. Tumors compact their circulatory system. This compression makes them even tougher with the medicaments being introduced.

The article goes on to state that most people think that a tumor is a simple set of cancer cells. According to dr. Jain, another researcher, has only 50% cells in a true tumor. The other half is made up of blood vessels2 and interstitial space. According to this scientist, the interstitial space in a tumor resembles the spaces between the marble in the box.

In addition, this article states that whatever the biological agents are mixed and administered, they must diffuse through the vascular walls and then diffuse through the interstitials to reach the target cancer cells. This article also states that all tumors are different from each other, each tumor has different areas. In addition, tumors change as they grow and their parts regroup. Most of the blood vessels inside the tumor are very disordered, twisted, twisted, adult with close blood vessels.

According to dr. Jain, because the tumor grows, its outer parts overgrow with new blood vessels from the surrounding normal tissue. In addition, there are few abnormal blood vessels that are derived from the tumor itself. Because the tumor grows in a limited space, most of the twisted blood vessels close to the center of the tumor are destroyed. Likewise, tumor cells that are close to these blood vessels obviously also die, although they can actively grow and form a cancerous tumor when transplanted into other animals. These areas of necrosis were subjected to high pressure. In the interstitial space, blood vessels r: liquid plasma are compressed. this pressure to penetrate the central areas of the tumor after circulating substances, including oxygen.

Nor is the pressure in normal tissues uniform. , and according to dr. Jain, big molecules like u ·the ends are reached by convection, which is due to pressure differences. Inside the tumor where pressure; higher, this convection does not occur.

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In addition, according to dr. Jain, the molecules migrate by diffusion, a mechanism similar to the spread of ink droplets in water.

Dr. Jain performed diffusion studies on the antibody in the tumor, finding that it would take days, months, or years to diffuse such large molecules into the tumor by diffusion. But such a long time is unsuitable for successful treatment.

The fluid formed in the interstitium slowly flows out of the tumor, along with the molecules diffusing into the center of the tumor.

In its Canadian patent application no. The authors of US 568512 describe a novel composition for treating cancer in combination with other therapies but such as thermotherapy (hyperthermia) and, if desired, therapies such as chemotherapy (or irradiation), e.g. , is a pharmaceutically acceptable carrier and active ingredients:

(a) a glucose-inhibiting amount of an active substance (non-toxic) that blocks a protein that transports glucose (active molecule-carrier) to the membrane and prevents glucose transfer to the cell and (b) an effective non-toxic amount of the drug that (i) improves penetration; enhances drug delivery through tissues surrounding various cellular elements, commonly known as scar tissue or fibrinous tissue, which is about a cancerous tumor, and (ii) alters the permeability properties of the tissue surrounding the tumor, which facilitates delivery of the drug to (a) the center of the tumor.

The authors also describe a combination and composition for treating cancer; this composition consists of:

(a) a glucose-inhibiting amount of the active substance (non-toxic), which blocks the protein that transports glucose (active molecule-carrier) to the membrane and prevents glucose transfer to the cell, and (b) an effective (non-toxic) amount of the drug that (i) improves permeability and increases drug delivery through tissues surrounding various cellular elements, most commonly known as scar tissue or fibrinous tissue, which is about a cancerous tumor, and (ii) altering the permeability properties of the tissue surrounding the tumor, which facilitates drug delivery to (a) the center of the tumor.

Following administration of a composition or combination containing drugs (a) and (b) to the placenta with metabolically active tumor cells, the tumor and cancer cells and their components are suppressed by thermotherapy (hyperthermia). Therefore, it can be argued that drug substance (a) enters the tumor cells and suppresses the tumor cells, which is an inadequate amount of glucose required for metabolism in cancer cells. In this way, the tumor cells disintegrate and die due to lack of energy. The authors of the present application disclose a method of treating cancer which is administered (e.g., with a pharmaceutically acceptable carrier):

(a) a glucose-inhibiting amount of an active substance (non-toxic) that blocks a protein that transmits glucose (active molecule in a carrier membrane) and prevents glucose uptake into the cell, and (b) an effective (non-toxic) amount of the drug that (i) improves penetration and increases pharmacy f

transporting material through tissues surrounding various cellular elements, commonly known as scar tissue or fibrinous reaction media, which are about cancerous tissue, and (ii) altering the permeability properties of the tissue surrounding the tumor, which facilitates drug delivery (a). ) into the tumor center by exposing the cancer cells to thermotherapy (hyperthermia). In some cases, other treatments (such as chemotherapy and / or radiation) may be used.

A glucose-inhibiting substance that blocks a protein that transports glucose into cells (cancer cells have higher levels of glucose than normal cells) can be used to:

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B'D'Glucose or analogues thereof, including floridizine glucuronide, 4-deoxifloretin-2-D-glucoside and the like.

An effective amount of the following active ingredients enables:

(i) enhancing the permeation and delivery of active ingredient (a) through tissues surrounding various cellular elements known as scar tissue or fibrinous reaction media around a cancerous tumor; and (ii) alter the permeability properties of the tissue surrounding the tumor, facilitating the penetration of the active agent into the tumor center, the active ingredients being dimethylsulfoxide (DMSO), methylsulfonylmethane (MSM) (also called dimethylsulfonmethane) or other molecular carrier type carriers; who are able to:

(i) enhances the permeation and delivery of the active ingredient (a) to the periwinkle, which surrounds various cellular elements known as scar tissue or fibrinous reaction media around cancerous tissue; and (ii) altering the permeability properties of the tissue surrounding the tumor, which facilitates penetration of the active agent into the tumor center.

Toxic drug tamed to be stil potent, published in Ontario Medicine, Vol. 3, no. 16, 1989 discloses the use of a drug substance in the liposome delivery system for delivery to a target area in a capsule containing a highly toxic but at the same time highly effective anti-fungal agent and illustrates how a toxic drug substance can be combined with a non-toxic drug substance. forms, avoiding - the danger of using.

This article states:

Initially, we believed that liposomes could transport almost all of the active ingredients to the target region 3545B. But research in the field over the last two decades has shown that these artificial cell-sized spheres can spontaneously form with only a small subset of the drugs currently in use, thus severely limiting their use.

Hoffer studied the effects of ascorbic acid (vitamin C) on a patient's health. In his article, he described the effect of vitamin C in the treatment of cancer. He also discusses Cameron's and Pouling's recommended use of 10cascorbic acid in the treatment of cancer patients, whose use increases the survival of patients with advanced cancer. Hoffer also points out that using ascorbic acid even at very high doses is not dangerous. 11 pages of his research. ascorbic acid is stated to be water soluble, capable of hydration but not LD₅₀. Hoffer notes that:

If the vitamin is not completely adsorbed from the gastrointestinal tract, it will hydrate in the intestines, causing diarrhea that will be watery but not dangerous unless it causes dehydration; which will force patients to reduce their dose quickly. At such doses it was used in the millions. Patients who have taken 30 g daily for 30 years are known. More dangerous than the same tablet salt. This remedy does not cause stone formation in the kidneys, does not cause malignant anemia, fertility in women and cancer.

The present invention relates to compositions suitable for the treatment of diseases and conditions.

Other objects of the invention will be apparent to those skilled in the art from the following description of the invention, in which applicants cite literature which does not disclose their invention.

Hyaluronic acid is a naturally occurring glucosoamine glycan. It has a molecular weight of up to 50,000 D and above and has high viscosity solutions. From a biological point of view, the molecular weight of hyaluronic acid is uncertain: determination of the molecular weight of hyaluronic acid results in various values ​​depending on the method used, the source from which it is obtained, the method of isolation, etc. The specified acid is found in animal tissues such as cerebrospinal fluid, articular ointment, rooster, skin, and in some streptococci. Different types of hyaluronic acid were obtained. U.S. Patent 4,141,973 discloses the preparation of a so-called high purification hyaluronic acid which does not cause any. side effects, used as an anti-inflammatory agent; The stated hyaluronic acid had a molecular weight of more than 750,000 D, apparently 1,200,000 D, and was used for the treatment of various joint diseases.

U.S. Patent 4,801,619 is about hyaluronic acid having a molecular weight of about 3x10⁶ D or higher, it is injected into the joint, thereby reducing the amount of proteoglycan in the joint lubricant to normal. The fact stated in this patent has a positive effect on proteoglycan metabolism in the joint. This patent states that hyaluronic acid may be used in the treatment of inflammatory disorders as well as in the treatment of degenerative disorders that occur with the use of symptomatic agents such as corticosteroids. In this way, it is clear that a sufficiently high molecular weight hyaluronic acid equals and counteracts the side effects that may occur with corticosteroids or other symptomatic agents producing analogous effects. The use of corticosteroids increases the amount of hyaluronic acid in the joint lubricant according to this patent and therefore, as stated by the inventors, their hyaluronic acid preparations have a beneficial effect on clinical symptoms such as joint pain, swelling and injury.

The patent states that the authors achieve their goal by introducing an effective hyaluronic acid having an average molecular weight of 3x10⁶ D, preferably a molecular weight greater than 4x10⁶ D, but the molecular weight should not be greater than 7x10⁶ D, - the amount inside the joint. The preferred dose of hyaluronic acid is 5 mg to 30 mg. The amount of aqueous hydrochloric acid or saline used in each injection is usually less than 60 ml, for example less than 20 ml. Typically, a 2% (w / w) solution diluted in buffer to physiological pH is used for injection, for example as a water-soluble sodium salt. The exact amount depends on the particular joint being treated.

The Merck index Specifies that the hyaluronic acid has a molecular weight of 50,000 to 8x10⁶ D, depending on the source from which it is derived, the method of preparation and the method of determining the molecular weight. Merck's publication also states that hyaluronic acid is used in ophthalmic surgery.

U.S. Patent 4,808,576 states that hyaluronic acid is a well-known remedy for preventing post-traumatic joint complications when applied directly to the affected tissue, if it is applied to the site where the damaged tissue was removed, or if it enters the affected tissue. location due to processes occurring naturally in the animal's body. In this way, the stated hyaluronic acid according to the claimed patent can be administered in any therapeutically acceptable form and by any stanLT 3545 B dartic route, for example, intravenously, intramuscularly, subcutaneously and externally.

Therefore, as stated in the patent, the use of hyaluronic acid becomes more convenient and attractive. For example, according to the patent, arthritis treatment of horses or humans does not require complicated joint injections.

U.S. Patent 4,725,585 describes a method of enhancing or regulating the body's immune system, which is based on the administration to a mammal of a therapeutically effective amount of hyaluronic acid.

The first column, lines 43-46, states that the finding of 15 is based on the unexpected discovery that the introduction of hyaluronic acid in mammals significantly enhances immunity.

The patent in question uses hyaluronic acid from Hilon TM (Pharmacia AB, Uppsaia, Sweden).

Pharmacia AB is also entitled to profit from US patent 4,141,373. The first column (line 19) states that if the infectious disease of the patient is healing poorly, hyaluronic acid and an antibiotic have been introduced in place of the hyaluronic acid used to enhance the patient's immunity. Although the patent states that the antibiotic was administered in combination with hyaluronic acid, but in fact because of the subcutaneous administration of hyaluronic acid and the patient having heart disease, it is clear to those skilled in the art that any anti30 biotic is administered separately, although it may also be administered intravenously (apparently) or muscle (less likely). In this way, (more likely) hyaluronic acid was introduced, according to the patent, to prevent other infections and enhance immunity, but not for other purposes.

U.S. Pat. No. 4,636,524 discloses structured gels of hyaluronic acid, whether pure or with other hydrophilic polymers, containing various materials or covalently bonded low molecular weight compounds, and methods for obtaining these gels. These products, as claimed in the patent, can be used in a variety of applications, including cosmetics and drug delivery to targeted areas.

In addition, the patent states that hyaluronic acid is known as a bio-tolerant polymer, that is, when administered to humans, does not elicit an immune response, so that structured hyaluronic acid gels can be used for a variety of medical purposes. Structured gels modified with other polymers or low molecular weight compounds can be used as drug delivery agents according to the patent. For example, the authors found that the incorporation of heparin into a structured hyaluronic acid gel retains its antithrombolytic activity.

The authors also claim that they have also found that structured hyaluronic acid gels can attenuate the release of low molecular weight compounds dispersed in gels covalently bound to a macromolecular gel matrix.

U.S. Patent 4,736,024 describes novel topical formulations containing:

(i) a pharmacologically active substance or a mixture of pharmacologically active substances for topical use; and (ii) an excipient suitable for external use containing hyaluronic acid or a fraction of hyaluronic acid or an alkali metal, alkaline earth metal, magnesium, aluminum, ammonium salt or pharmacologically active substance. material which may not necessarily be used with additional fillers suitable for external application.

The authors of this application refer to the recently published Japanese Patent 6,100,0017, issued January 6, 1986, which discloses that the patent encompasses the use of hyaluronic acid or structured hyaluronic acid or a salt thereof as an active ingredient for inhibiting metastasis of carcinoma.

According to the aforementioned patent, more than 1.0% of hyaluronic acid was dissolved in alkaline water with a solvent, preferably more than 50% tbo, and dioxane in an organic solvent such as alcohol. The preferred pH is 12-14. The multifunctional epoxy compound was then added and the reaction was carried out. 10 ° to 60 °, preferably 20 ° to 40 °, for 24 hours. The amount of transverse bonds in the structured hyaluronic acid and its salt was adjusted by changing the molar ratio of hyaluronic acid or its salt to the multifunctional epoxy. It is desirable that the viscosity of the hyaluronic acid be 0.2-30 and the molecular weight 4,000-2,000,000 D. According to the patent, the hyaluronic acid is used in several pharmaceutical forms. The clinical dose of hyaluronic acid or structured hyaluronic acid was usually 25 mg - 5 g / day (after) and 10 'mg - 2.5 g / l (injection). The patent reference states that hyaluronic acid, unlike other anticancer agents, has no side effects and has analgesic and tissue repair properties.

European Patent 0295092 describes the use of hyaluronic acid fragments with a filler as a transport system for delivering these fragments to the skin dermis when applied to the skin, for effect on blood vessels and for stimulating or restoring hair growth. Preferably, the hyaluronic acid moieties are polysaccharides containing from 7 to 25 monosaccharide molecules. According to the patent, it is clear that the longer the hyaluronic acid moieties, the more difficult it is to transport these moieties to the dermis, unless these moieties are part of a composition designed to increase the activity of these moieties.

In this way, a combination may be used to increase the activity of the hyaluronic acid moieties, and in particular, to increase their penetration through the skin when applied. Some enhancement of activity may be exerted by the use of fillers for hyaluronic acid moieties, as claimed.

Some activity enhancers, according to the patent, are capable of stimulating or enhancing hair growth. Minoxidil can be used as a booster among all other enhancers. In this way, hyaluronic acid fragments and minoxidil are used to stimulate hair growth.

European Patent Application 0179442 states that where there is a significant amount of free radicals, hyaluronic acid is degraded or degraded before its positive effect.

Canadian Patent 1,240,929 discloses a combination of a chondroitin sulfate compound and a hyaluronate for the protection of traumatic layers of tissues and tissues of animals and humans.

European Patent Application 0208623 describes the use of hyaluronic acid to increase the activity of some proteinases. The application also describes the use of hyaluronic acid in the treatment of connective tissue diseases, including malignant tumors and cardiovascular disorders.

European Patent Application 270317 describes a combination of an antiviral agent, an inhibitor that is not sufficiently inhibited, and a compound (e.g., hyaluronic acid) which exhibits antiviral activity, inhibits cell adhesion and / or inhibits the adsorption of viruses, used to treat viral diseases.

U.S. Patent 4,840,341 describes the use of an effective amount of hyaluronic acid as an active ingredient in pharmaceutically acceptable carriers, diluents or excipients for the treatment of retroviral diseases.

U.S. Patent 4,851,521 and European Patent Application 0265116 describe hyaluronic acid fractions, structured esters of hyaluronic acid, and their preparation. U.S. Patent No. 4,851,521 describes the administration of hyaluronic acid esters as an active ingredient and as a carrier for the formulation of pharmaceutical ophthalmic pharmaceuticals for external use (cf. column 11, lines 35-42 and column 12, line 62; column 13 Row 3) and as suppositories for systemic action through the skin.

Column 13 (lines 5-31) of the aforementioned patent states: The effect of the hyaluronic acid esters, when used as carriers, enables them to be used as adjuvants in the above-mentioned formulations, where the active ingredient is active not only by topical application or nasal or rectal absorption, for example by spraying or inhalation, but also by oral administration. bypassing the gastrointestinal tract, for example by intramuscular, subcutaneous or intravenous administration, as such administration is favorable for absorption of the drug at the site of administration. Therefore, the new drug can be used in a variety of medical applications such as in the treatment of internal diseases such as cardiovascular disease, respiratory tract infections, gastrointestinal, kidney, endocrine, oncology, psychiatry, etc .; and therefore these drugs may be classified according to their specific activity into anesthetics, analgesics, anti-inflammatory agents, wound preparations, antimicrobial agents, adrenergic antagonists, cytostatic agents, antirheumatic agents, hypotensive agents, urinary agents, sex hormones and immune 15 immunodepressants; for example, one of the medicaments having the described activity for the therapeutically active syrups used as the esterification component of the present invention or the therapeutically active bases used for the salification of the free hydrocarbon groups ...

Furosemide inhibits sodium resorption in the ascending nephron loop in its proximal and distal compartments. The effect of the medicinal product is independent of the inhibitory effect of carbonic anhydrase or aldosterone. Furosemide is a known drug that stimulates diuresis and is used when resistance to other diuretics is observed. This medicinal product has effects on renal function only and has no other pharmacological action. In the human body, it is absorbed through the gastrointestinal tract. Usually, diuresis is observed after 30 minutes of intravenous administration and lasts for approximately 2 hours.

Under various circumstances, the patient may develop relative resistance to the effects of lasik. This can happen for a variety of reasons, but most often this one

The phenomenon I is observed as the accumulation of large amounts of fluid in the peripheral water, which develops due to malnutrition and / and progressive carcinoma. In the latter case, a marked decrease in albumin levels is observed and apparently an increase in permeability and fluid transduction from blood vessels. As a result, such patients exhibit relative resistance to any type of diuretic, including laxative, even at high intravenous doses.

Extensive studies have been conducted to determine the body's immune deficiency, which is involved in the development of tumor cells. Jerne, and then Bernett, said the immune system is crucial for immuno-intelligence in killing atypical cells. This concept, while it seems simplistic, remains appropriate to explain the complex mechanism of immune recognition and the immune function of higher mammals.

In addition, tumors are thought to develop due to local or general immune suppression. But according to Moilor, if total immunosuppression occurs, only some types of tumors usually develop, mainly tumors of the lympho-reticular system. This observation is supported by symptomatic and immune studies, though in individual cases, and can often explain why cancer cells develop independently of the immune system.

1974 Experiments carried out in the year 2000 showed that phagocytic function is impaired in tumors.

In initial experiments, suppressor cells that were part of the immune system were detected; they are T-cells of the phagocytes. They are observed in neoplasia, in chronic bacterial infections, in the treatment of major injuries and in chronic fungal infections.

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Animal experiments have confirmed altered phagocyte function in neoplasia. Apparently, in living organisms, macrophage function is blocked in these conditions. Most of all, if these cells are removed from the in vivo medium, washed with saline and cultured, their function is normalized. Such blocking appears to be excess prostaglandin production by the tumor cells or blocking of the phagocytes themselves.

Major studies in the last 70 and 80 years have major contradictions about the role of immunotherapy in the treatment of cancer. Macrophage activation or aggression apparently also plays a role. But in the study of Romas and Fox peritoneal macrophages from cancer patients, it was found that macrophages that had already been activated interacted with the cancer cells and caused their destruction.

Earlier this year, independent researchers demonstrated that macrophage deficiency or putative blockade of their function is a consequence of excess prostaglandin production, which could be eliminated by corticosteroids, AA, non-steroidal anti-inflammatory drugs such as indomethacin and naproxen (trade name Naprosyn). In addition, in animal tumors, it has again been shown that the response of these substances to tumor cells may be altered, and that various combinations of these agents with immunostimulatory agents can provide reliable success in inhibiting experimental tumors. For example, combining indomethacin with interleukin-2 therapy, Lala and colleagues have shown that good results can be achieved in the treatment of experimental tumors.

The use of any of the aforesaid preparations in human in vivo experiments poses a real risk. All non-steroidal anti-inflammatory drugs (NSAIDs) are highly toxic when they enter the gastrointestinal tract, into neurological and other areas of the body. Thus, the present method is based on the fact that the said preparations penetrate into the pathological tissues in sufficient quantities and, when introduced into the affected human body, alter the local production of prostaglandins. As with the intravenous administration of indome, tacin and other drugs, it has been observed (as in the experiments of the authors of the present invention) that the separate administration of these agents causes unacceptable side effects in the human body.

Therefore, only small amounts of the indicated preparations can be administered to the human body, which results in a larger than accidental reaction in neoplasms.

However, there are many facts that suggest the cause of tumor formation and the immune primary cell intelligence mechanism associated with prostaglandin production. According to this postulate, it is only necessary to replace the amount of prostaglandin synthesized by the cells when they become malignant in order to determine the mechanism of blocking of the primary cell in the event of any immune response, that is, a macrophage. Therefore, it is essential to develop a combination of NSPUPs for clinical use to enhance the immune response to tumors and other conditions associated with excess prostaglandin synthesis, which is a pathogenesis of some states such as arthritis and others known as inflammatory connective tissue disorders and / or auto-aggressive states, reason.

See also the following works:

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1. Modulation of Immunity in Cancer Patient by Prostaglandin Antagonists, Immunity to Cancer II, Alan R., Liss, Ine., And

2. Goodwin JS (1981) Prostaglandin E and Cancer

Growth Potential for Immunotherapy with Prostaglandin Synthesis Inhibitors, Augmentative Agents in Cancer Therapy, Raven Press, New-York.

U.S. Patent 4,711,780 describes a pharmaceutical composition containing zinc salt of vitamin C, a sulfur-containing amino acid for the treatment of superficial epithelium for regeneration. The genital tract may be treated with hyaluronic acid as described in the patent.

Japanese Patent 63/0452223 relates to the treatment of retroviral diseases. As stated in the patent, hyaluronic acid is used to prevent or treat leukemia or AIDS by inhibiting viral replication.

In an article by Samuel Asculai entitled Antimicrobial Agents and Chemotherapy, entitled Inactivation of Herpes Simplex Viruses by Nonionic Surfactants, April 1978, p. No. 686-690 describes nonionic surfactants, such as nonoxygenase, detected in Delfen, which contain ether and amide linkages between hydrophilic and hydrophobic moieties and rapidly inactivate herpesvirus. This nonionic surfactant (PAM) activity is based on their ability to dissolve lipid-containing membranes. This fact is confirmed by studying the surface destruction of mammalian cytoplasmic membranes and the herpesvirus envelope surface by surfactants. Proprietary vaginal contraceptives containing nonionic PAM also inactivate the herpes virus. These studies suggest that the nonionic PAMs contained in the respective formulations could effectively protect against herpesvirus transmission.

Brief Description of the Invention

The present inventors have found that combinations or compositions (e.g., injectable preparations) can be administered for administration to mammals in the treatment of diseases and conditions in therapeutically active non-toxic amounts; these specified combinations and compositions may include pharmaceutical and / or therapeutic agents for the treatment of diseases or conditions (e.g., free radical acceptor), such as ascorbic acid (vitamin C), vitamin C (for the treatment of mononucleosis), anticancer agents, chemotherapeutic agents, antivirals (eg non-ionogenic PAMs such as nonoxynol-9 / nonylphenoxypolyethoxyethanol / it contains contraceptives in Delfen), anionic PAMs (such as pyridine hydrochloride) and cationic PAMs (such as benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSPUPs) (such as indomethacin, naproxen and (+/-) ketorolac tromethamine salt (tradename Toradol) and steroidal anti-inflammatory drugs, preparations, deintoxicants (for example, enema rectally) analgesics, broncholitics, antibacterial agents, antibiotics, preparations for treating vascular ischaemia (eg in diabetes and Bergeroligia), monoclonal antibodies, minoxilide for topical use for hair growth, diuretics (eg furosemide, trade name Lasix), immunodepressants (eg cyclosporins), lymphokines (such as interleukin-2, etc.), alpha- and beta-interferons, etc., which are introduced together with a certain amount (or amount) of hyaluronic acid and / or its salts (e.g. sodium salt) and / or homologues, analogs, derivatives, complexes, esters, fragments, and / or subunits of the specified hyaluronic acid ( preferably hyaluronic acid and its salts) sufficient to facilitate the transport of the active ingredient through tissues (including scars) at the site of application through cell membranes to individual target cells. unexpected improvement in the patient's condition is observed with the introduction of the indicated combinations and compositions for patients with various diseases and disorders.

The compositions of the present invention may be administered intravenously, arterially, intra-abdominally, pleural, dermally, topically, rectally, orally, or by direct injection, for example, into a tumor, abscess or analogous site of disease or by applying a swab to a patient's skin. . Hyaluronic acid and / or its salts and pharmaceuticals may be administered separately, but should be in sufficient amount for treatment and in the appropriate order, preferably together, more preferably simultaneously, at the same site (e.g. preparation on the other side).

The present invention provides a composition suitable for treating a disease or condition comprising a therapeutically effective non-toxic amount of a drug and / or therapeutic agent such as a free radical acceptor (e.g., ascorbic acid (vitamin C) for the treatment of mononucleosis), an anticancer agent, chemotherapeutic agent. (for example, non-ionic PAMs such as nonoxynol-9 (nonylphenoxyethoxyethanol), which is contained in the contraceptive paste Delfen, anionic PAMs (such as pyridine hydrochloride) and cationic PAMs (such as benzalkonium chloride); preparations, deintoxicants (for example, enemas for rectal administration), analgesics, broncholytic preparations, antibacterial agents, antibiotics, agents for treating vascular ischemia (such as diabetics and patients with Berger disease), monoclonal antibodies, minoxidol used to promote hair growth, diuretics (such as furosemide, trade name Lasix), immunodepressants (such as cyclosporins), lymphokines (such as interleukin) -2, etc.), alpha-beta-interferons, etc., which are administered together with a certain amount (or amount) of hyaluronic acid and / or its salts (e.g. sodium salt) and / or homologues, analogs, derivatives, complexes, esters, fragments, and / or subunits of the specified hyaluronic acid , preferably hyaluronic acid and its salts, sufficient to facilitate the transport of the active ingredient through tissues (including scars) at the site of application, through cell membranes to individual target cells.

To illustrate the facilitation of the transport of the chemical vehicle to the target mammalian area, an experiment was performed in which ethyl alcohol was injected directly into the tumor; ultrasound analysis showed that the alcohol introduced was not dispersed in the tumor. Subsequently, ethyl alcohol together with hyaluronic acid and / or its salts were introduced into the tumor; ultrasound analysis showed that ethyl alcohol was dispersed throughout the tumor.

Although the Applicants believe that hyaluronic acid facilitates the transport of pharmaceuticals, the present invention can still be used regardless of the mode of action of the hyaluronic acid and / or its salts and / or its homologues, analogs, derivatives, complexes, esters, fragments and subunits.

The combination of hyaluronic acid and its salts and other forms with various chemical compounds, such as vitamin C, anticancer agent, etc., affects their distribution in the human body and the clinical effect and provides targeted transport of the preparation to non-perfused and / or pathological tissue. For example, when using ascorbic acid (vitamin C) as a free radical acceptor (50 g / day 1000 times the daily dose for therapeutic purposes as a vitamin) administered intravenously with 300-500 mg of hyaluronic acid (hyaluronic acid sodium) immediately relieved pain in the bones and muscles and reduced the inflammatory process in cancer patients. Hyaluronic acid enhances the antitumor activity and effect of ascorbic acid. Obviously, this increased activity results in the binding of free radicals to free radical acceptors. In any case, the patient feels better. A similar phenomenon is observed with furosemide and hyaluronic acid; in this case, there is a slight increase in furosemide activity when this combination is administered to a normal body, but this activity is increased immediately when the given combination is administered to a patient with incompletely perfused kidney or with renal insufficiency due to insufficient internal volume.

A similar situation is observed in experiments with NSPUP. Because of the high amount of insoluble indomethacin required, the chemical product was dissolved in N-methylglucamine (NMGj to 5 mg / ml N-methylglucamine). This solution was then filtered through a 22 µm pore size filter to obtain sterile. the substance is non-toxic at a dose higher than therapeutic and therefore has been used in humans. Thus, for example, Indocide (trade name), reconstituted NMG, was administered to a human tumor (intraperitoneally, intraperitoneally, or intra-vascularly) at various doses up to 10 mg / kg, each dose of indomethacin was combined with 200-1000 mg of hyaluronic acid, e.g. Life Core (trade name) is a sodium salt of hyaluronic acid, diluted in indomethacin stock solution and NMG, in the same manner as Life Core. A mixture has been obtained which can be reliably introduced in any standard manner. Similar clinical studies have been performed with hyaluronic acid obtained by other means, ie extraction. The extracted material is preferably used

When introduced into a tumor, intraperitoneally or into the pleura.

Thus, in accordance with the present invention, when an NSPUP, such as indomethacin, dissolved in N-methylglucamine or another NSPUP, was co-administered with sugaryuronic acid in amounts greater than 200 mg NSPUP, 1 to 2 mg / kg body weight, indomethacin and NMG), no adverse events or intoxications, such as internalisation, neurological abnormalities, depression, etc., have been observed, even after administration of elevated indomethacin. When the amount of hyaluronic acid was lowered below this amount, the side effects reappeared. In addition, the enhanced response observed with NSPUP (e.g., Indocide) in combination with hyaluronic acid clearly illustrates that the indicated combination provides targeted drug delivery to the pathological tissue, even when administered intravenously as a standard. For example, in a patient undergoing cancer suspicion, 50200 mg (NSPUP - hyaluronic acid) of sodium hyaluronic acid, such as indomethacin and hyaluronic acid, were administered in addition to other che35 female agents (such as vitamin C, floretin and anticancer drugs). as a result, the pain disappeared immediately. After a short period of time, a reduction in malignant tumors and an improvement in lung liver function were seen in these organs. For example, death of tumor cells facilitates the removal of debris and tumor toxins from the body by macrophages, whose activity is increased by the administration of NSPUP (non-steroidal anti-inflammatory drugs) together with hyaluronic acid (or its salt or other form). Applicants thus believe that the addition of (NSPUP) non-steroidal anti-inflammatory drugs (NSAIDs) to hyaluronic acid (such as hyaluronic acid sodium) blocks macrophages by reducing the production of prostaglandins that block macrophage function. It can be concluded that hyaluronic acid (both its salt and other forms) not only increases the activity of NSPUP, but also reduces the side effects and toxicity that occur with the use of prostaglandin synthesis inhibitors.

A suitable example of a chemotherapeutic agent is posatron, mitoxetron, methotrexate, 5-FU (5-fluorouracil), carboplatin, methyl CCNU administered orally and mitomycin C.

In one case, methotrexate was coadministered with hyaluronic acid to the surface of the tumor tissue (e.g., the chest area) for a period of 5 to 7 days. Patient haematological scores were reduced by comparison with methotrexate, intravenous or oral doses of the same dose.

In addition, in most cases, when the tumor is disrupted using the treatment described above, the liver is unable to remove tumor toxins, debris and cellular debris, which results in death of the patient. In this case, it is possible to use not only hyaluronic acid with the corresponding NSPUPs, but also to introduce hyaluronic acid (hyaluronic acid sodium salt) with deintoxicants into the large intestine by enema.

Hyaluronic acid and its salt can be used in a variety of doses from 10 to 1000 mg per 70 kg of body weight, and the optimum dosage is from 50 to 350 mg per 70 kg of body weight. Since hyaluronic acid is non-toxic, it can be administered in excess (for example, 3000 mg per 70 kg bodyweight), and this dose does not cause side effects.

Thus, the present invention combines hyaluronic acid and / or salts thereof with cytotoxic chemotherapeutic agents, for example, or hyaluronic acid. It is administered immediately after administration of the indicated drug substance if it cannot be premixed or mixed prior to administration. The authors of the present invention used, for example, adriamycin, which was administered against hyaluronic acid, methotrexate, the two agents were mixed, mitomycin C, bleomycin, 5-fluorouracil, noventrone, carbo- and cis-platinum; mixed with hyaluronic acid - 10 mg of substance in 1 ml of hyaluronic acid, increasing to 100 ml and using the standard dose of the product.

As previously reported, the authors used drugs: floridizine, floretin, and 5-deoxyglucouronide fluoridizine in combination with dimethylsulfoxide for competitive blocking of glucose transport to isoglastic cells. The above drugs may also be combined with analogous doses of the above-mentioned chemotherapeutic agents hyaluronic acid using a reconstituted floretin such as N-methylglucamine.

I

For example, a combination regimen of ascorbic acid and oncostatin IV, dissolved in N-methylglucamine, florestin with a mixture of hyaluronic acid or a salt thereof, may be administered in a dosage regimen of 2-4 flo5 retinox, dissolved as described above, with 30-1000 mg or more. (overdose) with hyaluronic acid or its sodium salt. The above treatment regimen allows for a significant increase in drug permeation into tumor cells, resulting in a better outcome, especially when the tumors are glucose depleted and then suppressed by hyperthermia, chemotherapy and / or irradiation. Similarly, the aforementioned cytotoxic chemotherapy agents were combined with comparable doses of hyaluronic acid and / or salts thereof, and were administered intravenously, arterially, intraperitoneally or pleural, or by direct injection into a tumor under ultrasound or CT-control.

Other medicinal products in combination with hyaluronic acid and / or salts thereof may also be administered transdermally, such as insulin in diabetes, estrogen in menopausal women, progesterone for fertility control, and antimetabolites to prevent local infection such as acne occurring during for diphtheria bacteria. These remedies can also be used in combination with hyaluronic acid.

Intravenous administration of broncholytic preparations, such as aminophylline and theophylline, may also be carried out in combination with hyaluronic acid and / or salts thereof.

Administration of broncholytic medicinal products in combination with hyaluronic acid has been shown to increase the efficacy of the indicated medicinal products. Oral administration of medicaments with hyaluronic acid can also be used.

In one embodiment of the present invention, the present invention is a combination (nonionic PAMs such as nonoxylol-9 [nonylphenoxy-polyethoxyethanol] included in Delfen contraceptive paste) and hyaluronic acid and / or salt thereof and other forms for the treatment of:

(a) diseases caused by herpes viruses types I and II; (b) herpes, which causes symptoms to disappear suddenly and damaged tissue to recover.

The non-ionic PAM preferably has an ethereal or amide linkage between the hydrophilic and hydrophobic moieties, such compounds being much more active than PAMs having an ester bond or having an ether-ester bond.

The following are non-genomic PAMs and their relationships:

Surfactant (PAM) Communication

None (virus control)% nonoxynol (nonylphenoxypolyethoxyethanol) 1% Triton Χ-100 (n-diisobutylphenoxy-polyethoxyethanol)% Brij-97 (polyoxyethylene (10) oleic acid ether)% Span-20 (sorbitan monolaurate)

% .Span-30 (sorbitan monooleate)% Tween-20 (polysorbate 20)% Tween-80 (polysorbate 80)% Onyxol ether ether ether ether ether ester ether ether ester ether amide

If foreign bodies are introduced into the human body, such as drainage tubes, which must remain there, it is imperative that the surrounding tissue of the implant is not contaminated, usually after large amounts of antibiotics are introduced, the infection remains and the implant must be removed. The present inventors have found that when infected tissue surrounding the implant is treated with antibiotics containing hyaluronic acid (hyaluronic acid sodium), the infection is rapidly cleared and does not require removal of the implant.

The present inventors have also found that treatment of vascular ischemia (e.g., cancer with underfilled tumor tissue, diabetes, or Berger disease) when administered in combination with hyaluronic acid (hyaluronic acid sodium) increases the response to the drug.

In patients with tumors in the brain, the tumor shrinks. administration of dimethylsulfoxide (DMSO) less than 100 g / day with 10% hyaluronic acid (hyaluronic acid sodium salt) solution of 300-500 mg, reduces cerebral edema and spinal cord edema.

For the treatment of mononucleosis, the present inventors have successfully used vitamin C and hyaluronic acid in a patient with clinomania for a period of time, resulting in rapid recovery.

One form of hyaluronic acid and / or its salt, for example sodium salt and its homologues, analogs, derivatives, complexes, esters, fragments and subunits, preferably hyaluronic acid and its salts suitable for use in the present invention, was the fraction of hyaluronic acid produced by Sterivet Laboratories Limited. This product is a 15 ml vial of hyaluronic acid sodium, 20 mg / ml (Lot No 2F3 in 300 ml ampoule). The sodium salt of hyaluronic acid is a 2% solution having an average molecular weight of about 225,000 D. The water in this preparation has been three times distilled and sterilized according to the US Pharmacopoeia for Injection. Vials for hyaluronic acid and / or its salts can be used made of borosilicate glass, Type I, sealed with an inert stopper.

The fraction of hyaluronic acid and / or its salts, such as sodium and its homologues, analogs, derivatives, complexes, esters, fragments and hyaluronic acid subunits, is characterized by the following hyaluronic acid and its salts:

(a) The purified hyaluronic acid fraction, usually pyrogen-free, obtained from a natural source, is characterized at least by one of the following groups:

I) a molecular weight of 150,000 to 225,000 D;

II) less than 1.25% sulfonated mucopolysaccharides, by weight;

<td> 25</td><td>III)</td><td>less,</td><td>than</td><td>0.6% protein, total weight;</td>

<td></td><td>IV)</td><td>less,</td><td>than</td><td>150 ppm iron, all mass;</td>

<td></td><td>V)</td><td>less,</td><td>than</td><td>15 ppm of lead, all mass;</td>

<td></td><td>VI)</td><td>less,</td><td>than</td><td>0.0025% glucosamine;</td>

<td></td><td>VII)</td><td>less,</td><td>than</td><td>V. 0.025% glucuronic acid;</td>

<td> 30</td><td>VIII)</td><td>less,</td><td>than</td><td>0.025% N-acetylglucosamine;</td>

<td></td><td>ix)</td><td>less,</td><td>than</td><td>0.0025% amino acids;</td>

<td></td><td>X)</td><td colspan="2">extinction</td><td>the factor at 257 nm will decrease</td>

nis, than 0.275;

XI) an extinction coefficient of less than 0,25 at 280 nm; and

XII) pH 7.3 to 7.9.

Preferably, hyaluronic acid is water soluble and the average molecular weight of the hyaluronic acid is 150,000 to 225,000 D. More preferably, the hyaluronic acid fraction is characterized by a parameter from the group consisting of:

I)

II)

III)

IV)

V)

VI)

VII)

VIII)

IX)

X)

XI) less than 1% sulfonated mucopolysaccharides, by weight;

less than 0.4% protein, by weight;

Less than 100 ppm iron by weight; Less than 10 ppm of lead for the whole mass; less than 0.00166% glucosamine; less than 0.0166% glucuronic acid; less than 0.0166% N-acetylglucosamine; less than 0.00166% amino acids; an extinction coefficient less than 0.23 at 257 nm;

an extinction coefficient of less than 0.19 at 280 nm; pH 7.5 to 7.7.

Other formulations of hyaluronic acid and / or its salts and homologues, analogs, derivatives, complexes, esters, fragments and hyaluronic acid subunits may be selected by other manufacturers (see, for example, the description of prototypes above). The present inventors have successfully utilized hyaluronic acid sodium salt produced as Life Core Biomedical Ine., Which is characterized by the following parameters:

The Result parameter

<td>Appearance</td><td>Particles from white to creamy color</td>

<td>Smells</td><td>It has no noticeable odor</td>

<td>Average viscosity molecular weight</td><td>&lt;750,000 D</td>

<td>UV / Visual Evaluation, 190-320</td><td>Coordinated study</td>

<td>Optical density OD, 260 nm</td><td>0.25 pcs. OD</td>

<td>Identification of hyaluronic acid</td><td>Positive reaction</td>

<td>IR spectrum</td><td>Coordinated study</td>

<td>pH, 10 mg / g solution</td><td> 6,2 - 7,8</td>

<td>Humidity</td><td>max. 8%</td>

<td>Protein</td><td>&lt;0.3 µg / mg HU-Na</td>

<td>Acetate</td><td>&lt;10.0 µg / mg HU-Na</td>

<td colspan="2">Heavy metals, maximum quantities:</td>

<td>As Cd</td><td>Cr Co</td><td>Cu Fe</td><td>Pb</td><td>Hg Ni</td>

<td> 2,0 5,0</td><td> 5,0 10,0</td><td> 10, 0 25,0</td><td colspan="2"> 10,0 10,0 5,0</td>

<td>Microbial</td><td>pollution</td><td>There is no</td><td></td><td></td>

<td colspan="2">Endotoxins</td><td colspan="2">&lt;0.07 U / mg HU-Na</td><td></td>

<td>Biological</td><td>toxicity</td><td>Visual</td><td>test</td><td>was at-</td>

<td></td><td></td><td>lame</td><td>using</td><td>rabbits</td>

<td colspan="2">In the sources provided</td><td>are described</td><td>hyaluron</td><td>of acid</td>

<td>sources,</td><td colspan="3">the ways of obtaining and purifying.</td><td></td>

U.S. Patent 4,141,973 discloses fractions of hyaluronic acid, including sodium, which are characterized by:

(a) average molecular weight greater than 750 000 D, 10 preferably greater than 1 200 000 D, ie intrinsic viscosity greater than 1400 cm³/ g, preferably β greater than 2000 cm / g;

(b) a protein content of less than 0.5% w / w;

(c) an optical density of 1% hyaluronic acid sodium salt solution, measured at 257 nm, less than 3.0 OD and less than 2.0 OD, measured at 280 nm;

(d) a kinematic viscosity of greater than 1000 centistokes, preferably greater than 10,000 cS, in a 1% solution of hyaluronic acid sodium saline;

(e) molar polarization of less than 11x10 10 in saline solution of 0.1 to 0.2% hyaluronic acid in saline.³ grad. - cm²/ M disaccharide, measured at 229 nm;

(f) be free from any marked infiltration of the hyaline and anterior chamber of the eye, nor cause any inflammatory hyperemia in the mediastinal fluid, cause opacities or vitreous hyperaemia, or cause any pathological changes in the cornea, lens, iris, retina, retina, retina, retina intravitreal approximately 1 ml of 1% hyaluronic acid sodium salt dissolved in saline was introduced into the middle;

(.g) be sterile and apyrogenic; and (h) shall not show antigenic properties.

Canadian Patent 1,205,031, which is a prototype of U.S. Patent 4,141,373, describes fractions of hyaluronic acid having average molecular weights of 50,000 to 100,000 D; 250,000 to 350,000 D; and 500,000 to 730,000 D and methods of obtaining them.

PA

If high molecular weight hyaluronic acid or its salts or other forms are used, it must be diluted for intramuscular administration and to avoid muscle coagulation.

±0

Ascorbic Acid Injection (Vitamin C), US Pharmacopoeial Requirements, is manufactured by Steris Laboratories Ine., Phoenix, Arizona, 85045, USA, containing 22 mg / ml eq. 250 mg / ml of sodium ascorbic acid, in packs of 30 ml, 50 ml or 100 ml, preferably 35 ml.

For example:

the present inventors have combined hyaluronic acid and hyaluronic acid sodium salt and / or other forms thereof with pharmaceutical and / or therapeutic formulations of busern zuidatus.

treatment of diseases, and received an unexpected example:

Status or disease

Chemical and Medicinal

Cancer of macrophages

Free radical accoeptor, activity enhancer superoxide dismutase, ascorbic acid (vitamin C), anticancer agent, NSPUP, chemotherapeutic agents, deintoxicants eg cholestyramine

IA. Treatment of a tumor in the patient's brain

2. Hair growth

Dimethylsulfoxide (DMSO)

The combination of minoxidil is used externally for more active hair growth

3. Herpes, aphthous, stomatitis, shingles

4. Renal failure, heart failure, hypertension, edema

5. Infections, acne, mononucleosis

Nonionic PAMs such as nonoxynol-9, anionic PAMs such as pyridine hydrochloride and cationic PAMs such as benzalkonium hydrochloride

Diuretics - Furosemide

6th Transplanters

7th Inflammation, Removal of Tumor Remnants, Toxins, Cell Debris, Reduction of Side Effects, Pain Relief, eg, Back Pain

8th Deintoxication

Antibiotics, antibacterial agents, antimicrobials, ascorbic acid and hyaluronic acid

Cyclosporins

Non-steroidal anti-inflammatory drugs NSPUP eg diclofenan, indomethacin, cyroxicam, ibuprofen, ketorolac tromethamine salt, naproxen

9. ' Removal of bronchospasm

10th Vascular Ischemia

Enema, deintoxicants, peritoneal dialysis

Broncholytic agent, eg beclovetazondiproprionate, sodium chromoglycate, although this product is not considered a broncholytic agent, theophylline

Treatment of limbs in patients with diabetes, Berger's disease, etc. with appropriate medications such as trental

11th AIDS (HIV)

12th Diabetes

13th Postcard character and

14th A osis ai 'ge i ί .τη as from external infections

15th Tumor reduction

16th Hypertension, heart failure

17th Inhibition of prostaglandin synthesis

18th Increased perfusion oxygenation of tissues (for transplantation)

DMSO, Vitamin C, NSPUP eg Indomethacin, Naproxen, Ketorolac Tromethamine, Interferon, Vibromycin ™, Doxocycline - Tetracycline

Insulin

Estrogen Recovery

The main metabolite is, for example, sulfonamides

DMSO

Vascular calcium blockers, eg, nifedipine β-blockers, specifically ethenolol, propranolol

Acetylsalicylic acid

Perfuzate

In the treatment of cancer, the present invention provides a method of treatment and combinations of drugs and chemicals that increase the patient's life expectancy and psychological tone, even if the patient is responsive to standard treatments. The present inventors have successfully treated patients who have been post-treated for an increase in tumor decay rate, increased macrophage function, ability of the body subs to remove tumor cells, cell debris and toxins.

Examples

The following examples illustrate the present invention. For the most part, in all cases of cancer treatment, this treatment was given to patients who were refractory to standard treatment. Hyaluronic acid was also used in other forms in the examples provided, for example, as the sodium salt of hyaluronic acid.

Case I A patient with a pharyngeal epidermoid (squamous tumor type) of the year underwent initial surgical treatment with irradiation followed by hepatic metastases 7 years later. Two large tumors, 12 cm and 6 cm in diameter, were identified. Thereafter, she was treated with systemic chemotherapy with DMSO supplementation used to increase drug permeability, floretin dissolved in N-methylglucamine with DMSO supplementation used for improved penetration and direct injection of adriamycin, carboplatin and methotrexate into the tumor, in this case by injection and injection. supplemented with hyaluronic acid in a dose of 10 to 60 mg depending on the drug. No adverse reactions were noted and the patient was re-examined after 4 weeks. The smaller tumor was completely extinct. The larger tumor only consisted of a focal diameter of 5 cm, but without evidence of tumor presence, this was determined by biopsy. This case illustrates well the effect of hyaluronic acid as a drug carrier on the tumor, which facilitates tumor destruction.

Further Implications

Thereafter, the patient was administered 300 mg indomethacin and 300 mg hyaluronic acid daily; the patient was in remission but later died of an infectious disease.

Case II A woman with advanced malignant mealoma in the upper left thigh with enlarged groin lymph nodes, abdominal cavity, liver, lung and cerebral base, including cranial-cerebral norms. The primary tumor was removed, followed by a relapse that was not affected by cytotoxic or cytostatic chemotherapy because of the widespread tumor that the patient had considered incurable. Treatment was performed using a combination of floretin dissolved in N-methylglucoamine with hyaluronic acid at a dose of 10 to 50 mg / 2 -4 g administered intravenously for 5 days every 4 to 24 hours. The patient was additionally treated with thermotherapy for various tumor areas and supplemental systemic therapy using carbo-platinum with hyaluronic acid at a dose of 250 mg carbo-platinum plus methyl CCNU at full dose and mg administered by oral route for 5 days without in addition, she was systematically taking hyaluronic acid. Methotrexate mixed with hyaluronic acid was administered into a tumor on the left thigh or groin at doses of 37.5 mg and 60 mg hyaluronic acid, divided into two equal injections over two days. Thereafter (10-20 days), the patient underwent complete tumor regression in the upper thigh and groin, a marked improvement in liver function, a cyst-like tumor in the liver, usually measured as tumor shrinkage, and lung tumor disappearance. Regression of the base of the brain was observed, which was determined by the improvement of the nerve function of the head and the disappearance of the headaches. In this patient, the tumor was susceptible to most drugs and, at this stage, treatment resulted in a sudden onset of susceptibility to the same drugs but used in combination with hyaluronic acid, which, as can be seen from the example, acts as a drug transport agent.

Further Implications

The patient was further treated with floretin, indomethacin (NSPUP) and hyaluronic acid. This was followed by stable remission.

Case III is a year-old patient with gallbladder cancer, and the tumor has developed throughout the right liver. Previously, three repeated chemotherapy treatments were performed with the addition of DMSO, floretin with DMSO, and the direct administration of cytotoxic agents in combination with DMSO, as well as in combination with chemotherapy. Since May 1988, the patient has been treated with the same drugs but with the addition of hyaluronic acid as a carrier and dispersant, which are administered systemically and directly by injection into the tumor. The tumor shrank from the edges to approximately 20% of its original size and then began to shrink abruptly. Medicines used without additives when administered in a standard manner did not respond to this tumor.

Further Implications

Unfortunately, the tumor recovered, the patient died.

Case IV, a year-old patient with colorectal cancer with liver metastases, who had a solid tumor covering the entire right lobe and the middle left lobe, spread to the left lobe. The tumor was classified by surgeons as nonoperative. The PaLT 3545 B patient was treated with systemic chemotherapy, chemotherapeutic agents and floretin dissolved in N-methylglucamine with hyaluronic acid directly into the tumor two months earlier, as well as hyperthermia. The patient was treated for three days, injected directly into the tumor with cytotoxic agents and hyaluronic acid, and examined three weeks later. Ultrasound showed that the tumor had completely dissolved, leaving only a small piece of viable tissue; 500 cm of cyst tissue was obtained from the cerebrospinal fluid³ yellow fluid with tumor necrotic residues. This is an uncommon result of adenocarcinoma, which is known to respond slowly to medication. 30% of patients with these conditions were found to have disease progression with standard cytotoxic or cytostatic chemotherapy. The increased tumor destruction that occurred within three weeks was clearly due to the effect of hyaluronic acid as a drug carrier.

Further Implications

Tests revealed that the tumor had completely disappeared. But, after a while, the patient died of liver failure and pulmonary embolism.

Case V, a patient with neglected form of intercellular bladder cancer with metastases throughout the left pelvis and dilated nodes to the peripheral aortic, pancreatic, and overexcited areas, underwent surgery in combination with irradiation but relapsed; standard chemotherapy did not provide relief. The patient was treated with floretin, dissolved in N-methylglucamine, with the addition of hyaluronic acid, together with direct injection of carboplatin and methotrexate into the tumor tissues. Hyperthermia of tumor areas was also used. As a result of this treatment, a strong response with a febrile reaction was observed, due to tumor disappearance and bacterial excretion. This reaction was controlled by antibiotics and adequate hydration, monitoring the patient almost daily during this phase, showed a reduction in tumor size and halved after 7 days of treatment. This result is all the more impressive because the disease was in the inert state of all therapies, with the use of hyaluronic acid alone with other drugs that block glucose transport and the use of hyaluronic acid as a carrier of chemotherapeutic agents, delivered directly to the tumor.

Further Implications

Complete tumor necrosis was achieved. However, the patient died of an infection.

Case VI

A patient with an established tumor in the upper left part confirmed by biopsy was classified as nonoperative. It was known from the medical history that chemotherapy and irradiation had no effect. The patient was then treated with systemic chemotherapy using hyaluronic acid as follows:

<td>Date</td><td>Medicine</td><td>The dose</td>

<td> 05/10</td><td>Vinblastine</td><td>3 mg</td>

<td> 05/10</td><td>Mitomycin</td><td>3 mg</td>

<td> 05/10</td><td>Calcium leucovorin</td><td>40 mg</td>

<td> 05/10</td><td>5-fluorouracil</td><td>250 mg</td>

<td> 05/10</td><td>5-fluorouracil</td><td>250 mg</td>

<td> 05/10</td><td>Oncostatin IV</td><td>3 mg</td>

<td></td><td>Hyaluronic acid</td><td>10 mg</td>

<td> 05/11</td><td>Carboplatin</td><td>250 mg</td>

<td> 05/11</td><td>Vinblastine</td><td>5 mg</td>

<td> 05/11</td><td>Mitomycin</td><td>4 mg</td>

<td> 05/11</td><td>Calcium leucovcrin</td><td>40 mg</td>

<td> 05/11</td><td>5-fluorouracil</td><td>250 mg</td>

<td> 05/11</td><td>5-fluorouracil</td><td>250 mg</td>

<td> 05/11</td><td>Carboplatin</td><td>100 mg</td>

<td> 05/12</td><td>Vinblastine</td><td>2 mg</td>

<td> 05/12</td><td>5-fluorouracil</td><td>250 mg</td>

<td> 05/12</td><td>5-fluorouracil</td><td>250 mg</td>

<td> 05/12</td><td>Lekovorin</td><td>40 mg</td>

<td> 05/12</td><td>Oncostatin IV</td><td>2 mg</td>

<td></td><td>Hyaluronic acid</td><td>20 mg</td>

<td> 06/19</td><td>Mitomycin</td><td>5 mg</td>

<td></td><td>Hyaluronic acid</td><td>10 mg</td>

<td> 06/19</td><td>Vinblastine</td><td>5 mg</td>

<td></td><td>Hyaluronic acid IV</td><td>10 mg</td>

<td> 06/19</td><td>5-fluorouracil</td><td>250 mg</td>

<td></td><td>Hyaluronic acid</td><td>10 mg</td>

<td> 06/19</td><td>5-fluorouracil</td><td>250 mg</td>

<td></td><td>Hyaluronic acid IV</td><td>10 mg</td>

<td> 06/19</td><td>Calcium leucovorin</td><td>40 mg</td>

<td> 06/19</td><td>Oncostatin IV</td><td>3 mg</td>

<td></td><td>Hyaluronic acid</td><td>50 mg</td>

<td> 06/20</td><td>5-fluorouracil</td><td>250 mg</td>

<td></td><td>Hyaluronic acid</td><td></td><td> 10</td><td>mg</td>

<td> 06/20</td><td>5-fluorouracil</td><td></td><td> 250</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td></td><td> 10</td><td>mg</td>

<td> 06/20</td><td colspan="2">Calcium leucovorin</td><td> 40</td><td>mg</td>

<td> 06/20</td><td>Mitomycin</td><td></td><td> 5</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 10</td><td>mg</td>

<td> 06/20</td><td>Vinblastine</td><td></td><td> 5</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 10</td><td>mg</td>

<td> 06/20</td><td>Oncostatin</td><td></td><td> 3</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 50</td><td>mg</td>

<td> 06/21</td><td>Carboplatin</td><td></td><td> 20</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 10</td><td>mg</td>

<td> 06/21</td><td>.Methotrexate</td><td></td><td> 12,5</td><td>mg</td>

<td> 06/21</td><td>Carboplatin</td><td></td><td> 150</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 50</td><td>mg</td>

<td></td><td>Oncostatin IV</td><td></td><td> 3</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 0</td><td>mg</td>

<td> 06/22</td><td>Carboplatin</td><td></td><td> 150</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 10</td><td>mg</td>

<td> 06/22</td><td>Oncostatin IV</td><td></td><td> 3</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 50</td><td>mg</td>

<td> 06/23</td><td>Oncostatin</td><td></td><td> 3</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 50</td><td>mg</td>

<td> 08/16</td><td colspan="2">Calcium leucovorin</td><td> 40</td><td>mg</td>

<td> 08/16</td><td>5-fluorouracil</td><td></td><td> 300</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td>IV</td><td> 50</td><td>mg</td>

<td> 08/16</td><td>Carboplatin</td><td></td><td> 250</td><td>mg</td>

<td></td><td>Hyaluronic acid 1</td><td>IV</td><td> 100</td><td>mg</td>

<td></td><td>Oncostatin IV</td><td> 3</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td> 100</td><td>mg</td>

<td> 08/17</td><td>Carboplatin</td><td> 200</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td> 150</td><td>mg</td>

<td> 08/17</td><td>Carboplatin</td><td> 30</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td> 50</td><td>mg</td>

<td> 08/17</td><td>Edriamycin</td><td> 2,5</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td> 10</td><td>mg</td>

<td></td><td>Oncostatin IV</td><td></td><td>3g</td>

<td></td><td>Hyaluronic acid</td><td> 100</td><td>mg</td>

<td> 08/18</td><td>5-fluorouracil</td><td> 500</td><td>mcj</td>

<td></td><td>Hyaluronic acid</td><td> 100</td><td>mg</td>

<td> 08/18</td><td>Calcium leucovorin</td><td> 40</td><td>mg</td>

<td></td><td>Oncostatin IV</td><td></td><td>2g</td>

<td></td><td>Hyaluronic acid</td><td> 200</td><td>mg</td>

<td>Patient</td><td>was also treated</td><td colspan="2">floretin</td>

in acid. The following chemotherapeutic agents were added to the tumor in hyaluronic acid:

<td>Date</td><td>Medicine</td><td>The dose</td>

<td> 05-/11</td><td>Methotrexate</td><td>12.5 mg</td>

<td></td><td>Hyaluronic acid</td><td>58 mg</td>

<td></td><td>Edriamycin</td><td>1 mg</td>

<td> 05/21</td><td>Methotrexate</td><td>12.5 mg</td>

<td></td><td>Carboplatin</td><td>20 mg</td>

<td></td><td>Hyaluronic acid</td><td>10 mg</td>

<td> 08/18</td><td>Carboplatin</td><td>30 mg</td>

<td></td><td>Hyaluronic acid</td><td>50 mg</td>

08/18 Adriamycin 25.5 mg Hyaluronic Acid 10 mg

As a result of this treatment, the tumor, which was not healed by conventional means, was reduced by 50%. This proves that non-susceptible tumors can be treated with chemotherapeutic agents in combination with hyaluronic acid and / or its salts used as carriers of the indicated medicinal products.

Case VII A year-old patient with advanced breast cancer with palpated nodules in the supra-tactile area and enlarged inflammatory lymph nodes. The diagnosis was confirmed by biopsy. The patient was treated with combination systemic therapy and hyperthermic therapy, but this treatment was without significant improvement. It was then irradiated, starting in 1988. feature before 1989 January. Dr. Foko 1989 May 17 a study showed that such treatment was unsuccessful. After that, a massive exudate began to develop. Dr. Fok prescribed a combination of chemotherapy with hyaluronic acid, as follows:

<td>Date</td><td>Medicine</td><td>The dose</td><td></td>

<td> 05/16</td><td>Methotrexate</td><td> 25</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td> 10</td><td>mg</td>

<td> 05/16</td><td>Methotrexate</td><td> 25</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td></td><td></td>

<td></td><td>Aksila IT</td><td> 10</td><td>mg</td>

<td> 05/16</td><td>Methotrexate</td><td> 25</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td> 10</td><td>mg</td>

<td> 05/16</td><td>Oncostatin IV</td><td></td><td>3g</td>

<td></td><td>Hyaluronic acid</td><td> 20</td><td>mg</td>

<td> 05/17</td><td>5-Flucruracil</td><td> 250</td><td>mg</td>

<td> 05/17</td><td>5-fluorouracil</td><td> 250</td><td>mg</td>

<td> 05/17</td><td>Vinbiastin</td><td> 5</td><td>mg</td>

<td> 05/17</td><td>Mitomycin</td><td> 5.</td><td>mg</td>

<td> 05/17</td><td>Oncostatin IV</td><td> 3</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td> 30</td><td>mg</td>

<td> 06/02</td><td>Methotrexate</td><td> 25</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td> 30</td><td>mg</td>

<td> 06/02</td><td>The vinyl tin</td><td> 5</td><td>mg</td>

<td></td><td>Hyaluronic acid</td><td> 10</td><td>mg</td>

<td> 06/02</td><td>O n ko statin IV</td><td></td><td>3g</td>

<td></td><td>Hyaluronic acid</td><td> 30</td><td>mg</td>

<td> 06/05</td><td>5-fluorouracil</td><td> 250</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td> 10</td><td>mg</td>

<td> 06/05</td><td>5-fluorouracil</td><td> 250</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td> 10</td><td>mg</td>

<td> 0 6/05</td><td>Calcium leukemia</td><td> 35</td><td>mg</td>

<td> 06/05</td><td>Vinbiastin</td><td> 5</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td> 10</td><td>mg</td>

<td> 06/05</td><td>Oncostatin IV</td><td></td><td>3g</td>

<td></td><td>Hyaluronic acid</td><td> 30</td><td>mg</td>

<td> 06/21</td><td>Carboplatin</td><td> 20</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td> 10</td><td>mg</td>

<td> 06/21</td><td>Methotrexate</td><td> .12,5</td><td>mg</td>

<td> 06/21</td><td>Vinbiastin</td><td> 5</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td> 10</td><td>mg</td>

<td> 06/21</td><td>Mitomycin</td><td> 5</td><td>mg</td>

<td></td><td>Hyaluronic acid IV</td><td>10 mg</td>

<td> 06/21</td><td>Oncostatin IV</td><td>3 mg</td>

<td></td><td>Hyaluronic acid IV</td><td>30 mg</td>

<td> 07/10</td><td>Carboplatin</td><td>25 mg</td>

<td></td><td>Hyaluronic acid IV</td><td>20 mg</td>

<td> 07/10</td><td>Methotrexate</td><td>12.5 mg</td>

<td></td><td>Hyaluronic acid IV</td><td>20 mg</td>

<td> 07/10</td><td>Oncostatin IV</td><td>3 mg</td>

<td></td><td>Hyaluronic acid IV</td><td>30 mg</td>

<td> 07/12</td><td>Oncostatin</td><td>2g</td>

<td></td><td>Hyaluronic acid</td><td>50 mg</td>

<td> 08/14</td><td>Vinblastine</td><td>5 mg</td>

<td></td><td>Hyaluronic acid IV</td><td>50 mg</td>

<td> 08/14</td><td>5-fluorouracil</td><td>50 \ ng</td>

<td></td><td>Hyaluronic acid</td><td>50 mg</td>

<td> 08/14</td><td>Calcium leukemia</td><td>30 mg</td>

<td> 08/14</td><td>Oncostatin IV</td><td>3g</td>

<td></td><td>Hyaluronic acid</td><td>100 mg</td>

<td> 08/16</td><td>Oncostatin IV</td><td>3g</td>

<td> •</td><td>Hyaluronic acid</td><td>100 mg</td>

The patient also underwent pleural puncture and subsequent instillation of 5-fluorouracil, mitomycin C and hyaluronic acid into the thoracic cavity. The pleu5 rally exudate completely disappeared. The breast tumor continued to shrink, while the clavicle and lymph nodes completely disappeared.

This patient responded to a relatively low dose of hyaluronic acid and / or its salts added to standard chemotherapeutic formulations by systemic injection into the pleura. Response increased when TM was given in combination with floretma and Sinacid acid and / or its salt).

and instibut nau {hyaluron

Further Implications

Investigations performed after a long period of time indicated that stable remission was achieved.

In case VIII, a woman who had previously been treated with systemic chemotherapy had failed in combination with two different medicines. The patient was prescribed treatment: hyperthermia and direct chemotherapy injection, and a response was seen from September.

Between April and May, tumor growth in the upper left lung was observed. This tumor was er.plastic small cell carcinoma. The tumor was exposed to bleomycin with hyaluronic acid and injections of indomethacin with hyaluronic acid into the affected areas. The patient was also systematically administered 300 mg daily with 300 mg hyaluronic acid. Significant improvement was seen after 2-4 weeks following radiological treatment. From. a recent x-ray showed the left thorax was clean. No pleural reaction was observed on the right side. Compared with the previous x-ray, the tumor was found to be significantly reduced, but it was not possible to determine its exact size in this picture.

The present inventors state that the result obtained is the use of chemotherapeutic agents and non-steroidal anti-inflammatory agents (for clearing necrotic tumor tissues) in combination with hyaluronic acid molecule carriers.

Case IX

1988 In July 2002, the patient was diagnosed with non-operable gastric cancer. A bypass graft was performed according to the type of gastro-tomatosis. The patient was examined in August, and treatment began in September 1988. At the same time, hyperthermia and floretin were treated with very low doses of chemotherapeutic agents using 5-fluorouracil and immunostimulants.

This treatment was continued until February 1989, after which Dr. Fox began using DMSO as an agent carrier to increase penetration with ASN. The patient was given increased chemotherapy with 5F-leucoverin, mitomycin Chir methotrexate, then in July and early August, as the tumor progressed, the patient was also given nonatron.

In May, when the patient started receiving the prescribed preparations containing hyaluronic acid, the initial level of hyaluronic acid was very low, with the average dose being 10 to 30 mg with the parent drugs, ie floretin or chemotherapeutic agents. Initially, a slight improvement in the patient's condition was observed, but later in mid-August the tumor began to progress, causing gastric obstruction, including biliary obstruction with developing jaundice and elevated bilirubin in the blood. After that, dr. Fok prescribes a higher dose of hyaluronic acid - up to a full dose - of 500-600 mg of hyaluronic acid, distributed across all medications. The patient was given the same medication.

Although the patient's condition initially improved, a gastrointestinal examination in September showed that the artificial gastrointestinal tract was completely cleaned, although by this time any oral administration had caused the patient to vomit. From this point on, the patient's condition began to improve steadily.

Based on the fact that the patient had previously received identical drugs, it can be concluded that the improvement was due to an increase in carrier molecules enhancing drug penetration into an already scarred fibrotic tumor, usually fatal at this stage.

Further Implications

Unfortunately, after a while, the patient died of tumor necrosis and a developing red tumor, but not from cancer.

Case X

The patient was diagnosed with hepatoma, which developed for 2 years. The tumor was relatively stable or had minimal growth over the last 18 months. The patient was given low-dose chemotherapy with suhialuronic acid, after which the patient recovered completely. The alkaline phosphatase assay showed a concentration of 150 IU in the liver function test and was found to be near normal. Dr. Fok continued to repeat treatment every 2-3 months.

Further Implications

The patient feels fine.

Case XI

Patient 1989. 15 June was treated with the chemotherapeutic agent Suhialuronic Acid. Thereafter, hyperthermia was treated. The breast cancer diagnosed with liver metastases was rigid for treatment with tamoxifen, an estragon-blocking duck agent.

After the above-mentioned treatment within 8 hours, a complete response was observed. Ultrasound showed no tumor in the liver and liver function tests showed abnormal liver function.

While no additional treatment was required, the patient continued on tamoxifen to block the estrogen receptor.

Further Implications

A relapse was seen after another doctor prescribed a vaginal cream containing estrogen (temoccifene) for vaginal irritation. As a response, treatment was given with 300 mg indomethacin with 300 mg hyaluronic acid daily. This was followed by remission.

ΧΙΑ Case

1989 m. March 26 The patient underwent uterine resection for massive leomiosarcoma. But a CAT scan revealed a residual tumor. The doctor prescribed a combination therapy combining hyperthermia using a very low dose of methotrexate, administering it in the abdominal cavity with hyaluronic acid as a carrier, and then using an agent that blocks glucose-floretin, also in combination with hyaluronic acid, and using interferon alfa-IIi for intraperitoneal administration also with hyaluronic acid.

Further scan of the patient showed that the tumor was reduced because soft tissue sarcoma is highly resistant to all forms of treatment, results were unexpected and can be reliably attributed to the carrier hyaluronic acid. Further dr. Fox continued to treat the patient approximately every 3 to 8 weeks for 2 days, resulting in tumor regression.

Further Implications

Some tumors started to grow again. The patient was treated with vitamin C (50 mg daily), indomethacin 300 mg daily with 300 mg hyaluronic acid. This treatment made the patient feel better.

ΧΙΒ Case

The patient was treated with a relatively low dose of methylCCNU and carboplatin with methotrexate for administration to groin relapsed melanoma. All of these preparations were administered together with hyaluronic acid, a carrier, a penetration enhancer. In addition, the patient was treated with dr. A drug developed by Fock to block glucose transport. This medicine is called floretin and has been used for several years. Floretin was dissolved in a special solvent and was given in combination with hyaluronic acid, which increases the rate at which the medicine is delivered to the tumor. After that, dr. Fok treated hyperthermia with microwave hyperthermia using permeable and artificial radio frequency. In addition, the patient was given immunostimulatory drugs, which according to Dr. Foką is effective only with other medicines.

In the last 2 courses, the patient was treated only with carboplatin with hyaluronic acid, floretin with hyaluronic acid and methotrexal given in low doses of 25 - 35 mg, also in combination with hyaluronic acid.

Dr. Phok looked at the patient after a week and continued treatment for 2 days. Clinically, the patient was in good standing. The patient complained of pain in her left back. On examination, pain in the left kidney was found to occur. Ultrasound of the kidneys showed a solid mass in the left kidney, which was believed to be hamartoma or angioma.

Given the patient's strong response to treatment, dr. Fox performed a CAT scan of the abdomen. There was minor cystic damage to the right liver but liver function was normal.

Further Implications

The patient was monitored for stable remission.

Case XII

The patient underwent an arterial line and a subcutaneous entrance into the abdominal cavity during the primary surgery. He turned to dr. Focus on redness and swelling around the subcutaneous entrance. The patient had elevated temperature and elevated white blood cells.

A plasma vessel (L14) was introduced into this area and 75 ml of pus were drained, and E. coli and Pseudomonas aeruginosa were detected in these pus. Dr. Fox treated this damaged area by introducing ampicillin with hyaluronic acid, flagella hyaluronic acid, and keflosrine hyaluronic acid. The wound was treated daily with 50 mg flagin with 50 mg hyaluronic acid and 1 g Anęef with hyaluronic acid. For 2-3 days it was still possible to pump out the pus from the affected area. After 5 days, the abscess was gone and only fluid remained and at the end of the week there were no signs of infection. The catheter was left in the entrance for another three months.

This example demonstrates that the use of antibacterial agents in combination with hyaluronic acid results in a better penetration of the drug into the infectious area and is therefore a basis for claiming that the above combinations improve drug penetration into the bacteria itself.

Case XIII

1989 m. June 1 the patient underwent surgery for resection of the large intestine, sigmoid bowel, and small intestine. Swelling and induration of the operated tissues were observed for 7 days after surgery, which resulted in drainage of the abscesses at two sites. These areas were then treated with 1 mg of ampicillin with 50 mg of hyaluronic acid and 500 g of flagella along with hyaluronic acid. After 4 days, these two areas were cleared of bacterial contamination. Usually it takes a few weeks of treatment to achieve this result.

Case XIV

A patient with breast cancer had an infection in the Hickman line. A plastic catheter was inserted continuously into the vein above the clavicle. The infection referred to was localized subcutaneous abscesses, which were constantly leaking from the entrance to the plastic container. According to this dr. Fok injected 1 g of ampicillin with 50 mg of hyaluronic acid, injected directly into the catheter. In addition, the patient was treated with intravenous flagella containing hyaluronic acid. The infection cleared and the catheter was left for another 4 days.

Case XV

The patient was diagnosed with an abscess in the upper right abdominal cavity, on the anterior abdominal wall. The patient underwent drainage at the clinic but was unsuccessful. Dr. Fok prescribed treatment with ampicillin 500 mg with hyaluronic acid 200 mg (daily). Although abscess drainage is ultimately incurable, it usually takes a long time to prevent relapse. Abscesses were detected in Staphylococcus aureus and E. coli.

2 days after irrigation with ampicillin and hyaluronic acid, as described, the cavity was cleared, the infection disappeared, and granulation began. Treatment was continued for another week, after which the patient recovered.

In other patients, shingles and ulcers were administered a₂Interferon in combination with hyaluronic acid, patients also recovered rapidly after this treatment.

One patient had methotrexate with hyaluronic acid externally for the treatment of psoriasis. These^rthe combination of preparations was well absorbed and treatment gave good results.

Ten patients with simple herpes type I and type II were treated with an effective amount of nonoxynil-9 [nonylphenoxyethanol] (Delfen) with hyaluronic acid and / or its salts on the respective areas 2-3 times daily, resulting in immediate disappearance of pain and irritable places healed.

Two patients with shingles were given effective amounts of nonoxynil-9 with hyaluronic acid and / or its salts, which resulted in recovery.

Case XVI, a year-old dentist with melanoma, had shingles with skin lesions on the left side of chest area 9. The patient had severe pain that did not subside with the standard formulations. Dr. Phok prescribed the patient an oral cyclofur as an antiviral agent, which was immediately inactive. Then dr. Fok prescribed Delfen and Life core ™ (hyaluronic acid) mixed in various proportions, they were used externally. As a result, the pain disappeared after 5 minutes. There were no pains for the next 4 days. In addition, the skin lesions disappeared within 24 hours and did not recur within the next 5 days. This particular effect can be explained by the antiviral activity of the combination used, the effect of which is increased by the hyaluronic acid.

Case XVII

The patient had gastric cancer with liver metastases. He was treated for 7 months with chemotherapy at low doses of 5-FU, low doses of mitomycin and penetron with various amounts of hyaluronic acid, and vitamin C. No tumor was detected after the indicated treatment. remission with all tumors was performed.

Case XVIII

The patient suffered a major car accident, after which he quickly developed colon cancer with multiple liver metastases. He turned to dr. Phok, 1989 in June. Chemotherapy using floretin with hyaluronic acid and thermotherapy were performed. There were no significant treatment results over the years, and then alkaline phosphatase began to decline. Then dr. Fok prescribed vitamin C (50 g / day for three days), hyaluronic acid (up to 300 mg / day), indomethacin, dissolved in N-methylglucamine (300 mg / day) with 300 mg of hyaluronic acid, and Toradol (60 mg once or twice a day). per day) with hyaluronic acid (50 mg). After such treatment, relief was observed. Alkaline phosphatase increased and liver function improved.

Case XIX, a patient diagnosed with pulmonary alveolar carcinoma three months ago, was not treated with either chemotherapy or high dose irradiation, although she was treated with spot irradiation in two areas; skeletal lesions were visible on either side of the thorax.

The patient contacted a cardiopulmonary transplant unit in London, where he was told that the transplant could be done but had to wait one year in a row.

In case XX, the patient underwent surgery to remove the colon cancer. After surgery, right metastases of the liver were observed. She received methotrexate (25 g) twice with hyaluronic acid (400 mg) twice a month, administered intraperitoneally, oncostatin 5 times (2g) with hyaluronic acid (300 mg) and indomethacin (NSPUP) twice, (100 mg). indomethacin with i

(300 mg) hyaluronic acid and (250 mg) indomethacin with 500 mg hyaluronic acid.

The patient immediately felt better and the tumor in the liver regressed and contracted.

Case XXI A year old patient with uterine cancer with lung metastasis -leomiosarcoma. Dr. Fok prescribed treatment using a variety of low doses of oncostatin, from 0.5g to 3mg with hyaluronic acid (300-500mg), vitamin C (30mg) with hyaluronic acid (300mg), indomethacin with succaluronic acid (intraperitoneal and intravenous) ).

Pelvic tumors reg:: esa, lung tumors remained stable.

Case XXII years old patient with Crohn's disease with chronic intestinal infection as a consequence of Crohn's disease. As a result, the patient began to develop a tumor in the abdominal cavity, adenosarcoma. The patient was treated with (3 g) Oncostatin ™ (floretin) at each dose with hyaluronic acid (500 mg) and (DMSO) (2000 total). Indomethacin doses ranged from (75 mg) to (450 mg) with 200-700 mg of hyaluronic acid. The patient also received vitamin C (50 mg) with hyaluronic acid (300 mg) and naproxen (1 g) with hyaluronic acid (400 mg). This treatment was performed using several drug delivery routes: intraperitoneal, intravenous, rectal deintoxication (catheter insertion and rectal administration). The pain has disappeared as a result of this treatment.

The patient underwent a CT scan of the abdomen and pelvis. Moderate liver steatosis with no detectable metastases was diagnosed. The spleen, pancreas, adrenal gland and right kidney were normal. Left renal drainage after nephrostomy did not show residual hydronephrosis. A large necrotic tumor mass was observed, occupying the greater part of the pelvis, extending into the anterior wall of the bladder with little involvement of the prostate. There was no destruction of the sacrum, although the colon was close to its surface.

In this way, a large tumor necrotic mass was found without destruction of the sacrum, without para-aortic lymphadenopathy or without peripheral metastases in the internal organs. An ureothral bench (transdermal) was introduced.

The patient was examined (August 1990) and felt well. The necrotic mass gradually decreased and the patient's condition improved significantly.

Case XXIII A 'V patient was diagnosed in 1990. dry. Gastric resection was performed with replacement of the esophagus (for swallowing). There was also a noticeable tumor in the abdomen. Hair loss has occurred after chemotherapy treatment. Dr. Fock prescribed an external treatment with minoxidil with hyaluronic acid, and hair began to regrow. After examination in 1991 June 6 dr. Fok prescribed reduced doses of floretin with hyaluronic acid and vitamin C with hyaluronic acid. After this treatment, the patient experienced a significant improvement. Her weight increased, she felt no pain. The carcinoembryonic antigen decreased to 23 mg / ml and steadily decreased further.

I

Case XXIV patient first referred to dr. Fok 1988 On March 1, he was diagnosed with: pancreatic cancer. It was treated using (DMSO) in combination with thermotherapy and chemotherapy at low doses. DMSO and other drugs were administered directly into the tumor. Less than a year later, the patient was treated with vitamin C and other hyaluronic acid medications. This treatment resulted in stable remission. The patient had not taken any medication for more than 6 months.

Case XXV

Dr. Fox examined a 62-year-old patient in 1989. in August. The diagnosis was made: pancreatic cancer. Chemotherapy treatment was administered using low doses of 5-FU in combination with 300 doses of bile duct thermotherapy.

mg) with hyaluronic acid, dePatient complained of pain But during the operation, the tumor was not detected in the bile ducts, only a bile duct bypass was performed. Thereafter, the patient was treated with indomethacin and vitamin C with hyaluronic acid, and treatment with hyperthermia was discontinued. After this treatment, the patient gained weight and no detectable tumor was detected.

In case XXVI, a patient was treated for one year for infectious mononucleosis. Studies performed three months later showed a positive reaction to heterophilic immunoglobulin. The patient complained of severe weakness. Treatment was given using 50 g of vitamin C and 500 mg of hyaluronic acid. After 6 hours, the condition improved dramatically and the weakness disappeared. Heterophilic immunoglobulin assay was negative after two weeks.

In case XXVII, the patient was diagnosed with a tumor and received chemotherapy for a year. The therapists who performed the treatment were unaware that they had removed a large portion of the tumor. As the tumor was disrupted, as determined later by Dr. Fok, fluid accumulated in the tumor area (seen with ultrasound). Dr. Fok prescribed treatment with thermotherapy, floretin, vitamin C, indomethacin and a small amount of 5-FU, all of which were combined with hyaluronic acid. According to previous doctors, the tumor had grown from the use of 5-FU, leading to the discontinuation of chemotherapy. The patient felt better, and the swelling of the disappearing looked better.

Case XXVIII

The patient was diagnosed with ovarian cancer with complete bowel obturation, as if covered with a tumor and a large amount of plural fluid. In this case, the effective action of Lazix (furosemide) was observed, which was used as follows. 1990 April 23 and 29 the total urine volume excreted by the patient within 48 hours was 2450 mi, despite the addition of a 0.33% sodium chloride solution to the patient supplemented with potassium chloride at 40 mg-eq / l (10-1 ml per hour). The weight of the hospital was 40 kg. During this period, the patient was given intravenous Lazix (120-200 ml).

April 30 40 mg of salmon with 550 mg of hyaluronic acid was administered in half an hour. 2300 ml of urine was then excreted within 5 hours. In the evening, the patient was not given Lazix, which resulted in a sharp drop in urine output to 400 ml (from 7am on April 30 to 7am on May 1). 7 hours 30 minutes she was given intravenous 40 mg of Lazix with 300 mg of hyaluronic acid. Thereafter, the patient's urine output was 2600 ml within 8 hours. This fact demonstrates that, even in the presence of relative insensitivity to furosemide (lax), it can be removed by the addition of hyaluronic acid, which increases the penetration of the drug into the area.

A similar phenomenon has been observed in patients with so-called hepatorenal syndrome, where urine output is not due to renal insufficiency. In these cases, urine output may not occur at all. For intravenous administration of furosemide (Lazix^1M) with hia15 luronic acid produces surprising results, even when only one Lazix is ​​introduced without any effect.

Case XXIX

Following administration of furosemide (Lazix ') 20 mg (intravenously) with 300 mg of hyaluronic acid to healthy subjects, an increase in urine output of 3 to 4 times that of Lazix alone was observed.

This demonstrates that hyaluronic acid increases the permeability of drugs and facilitates their function.

Case XXX

The patient was treated for baldness by applying minoxidil (Rogaine) to the scalp. Was $_s only slight hair growth is observed. Minoxidil was then used with hyaluronic acid continuously every 2-3 days. As a result of this treatment, the patient's hair grew thicker and significantly faster.

Case XXXI

At the Kayo Clinic, a diagnosis was made after 32 years of examining a patient: epithelial-cellular sarcoma.

The onset of the disease dates back to 1978. on December 12, when a nodular tumor was seen on an unnamed finger in his left hand and the finger was amputated. After relapse, the 4th finger of the left arm was amputated. Following extensional examination, nodular oncology was detected in the upper arm and the auxiliary lymph nodes, which was confirmed in a biopsy in 1990. in March.

At Kay's clinic, the patient was treated with three courses of chemotherapy with vitamin C, adriamycin, high-dose cisplatin, but this treatment failed. The patient underwent amputation of the left arm and anterior quarter of the anterior penis.

Dr. The patient was examined by Fock in 1990. on June 25, and prescribed treatment with hyperthermia, floretin with hyaluronic acid, vitamin C with hyaluronic acid, methotrexate with hyaluronic acid, and also solododol, which were given for three days. The treatment was without visible results and there was no improvement.

The patient returned to the clinic on July 23 for three days with a reduced dose of floretin, the same dose of vitamin C with hyaluronic acid, the patient also received subcutaneous and intravenous naproxen and indomethacin with hyaluronic acid. The patient returned to the home where she was treated with Toradol [Syntax, a non-steroidal anti-inflammatory drug] (intramuscular), 30 to 120 mg daily, given once or twice a day with 100 mg of Hyal (dosage form hyaluronic acid).

The patient was examined on August 20 and found to have a 50% reduction in all lesions. In fact, no viable tumors were found at biopsy. Treatment was continued with Toradol with hyaluronic acid.

Although the patient was low susceptible to hyperthermia, floretin and standard combination chemotherapy and hyaluronic acid, excellent results were achieved with all types of non-steroidal anti-inflammatory drugs: Indocidas ™, naproxen and Toradol with hyaluronic acid as a carrier or excipient. , ensuring targeted drug transport to the pathological tissue. No adverse reactions specific to these non-steroidal anti-inflammatory drugs have been reported with the patient.

Case XXXII

1988 patient was diagnosed with stomach cancer in the year. The tumor was located in the distal third of the esophagus at the entrance to the stomach. In an intraoperative procedure, a Selestin tube was inserted over the abdominal cavity and sutured to a minor gastric flexion.

The patient has been treated since 1990. January three months and '90. was investigated in June. No changes were found in the repeated CAT scan; symptomatically the patient felt well. The last scan was made in 1990. June 26 Some parts of the liver were suspected of having lesions, but these findings were rejected by ultrasound.

July 4th during the picnic, the patient ate a sausage sandwich. At night he awoke from a sharp pain in his right side that was not accompanied by nausea and vomiting. After this episode, the patient felt constant pain while eating. This pain was constant, affecting the back and front of the abdomen and spreading sideways. This pain has never been directly associated with abdominal pain, vomiting, diarrhea, elevated temperature, tremor. A CT scan was performed just 8 days prior to the onset of pain and gastrointestinal examination was performed. An additional CT scan was not possible because the stomach was filled with barium compounds.

It should be noted that the prescribed dose of Demerol only partially relieved pain. Further investigations did not bring new results. No nodules were detected in the abdominal cavity, thoracic or lymphatic vessels which would indicate the spread of the disease.

Dr. Fox performed X-rays at a Toronto hospital with a professor of radiology. Studies of the upper gastrointestinal tract showed that a classic view of small intestinal adhesion was observed. In the doctor's opinion, this could be due to either fibrotic adhesion, malignancy, or both, which is often the case in gastric adenocarcinoma. However, apparently, neoplastic dissemination was insignificant as it was not detected at the last CAT scan.

Dr. Fock prescribed treatment to a patient in combination with a non-steroidal anti-inflammatory drug (NSAID) with hyaluronic acid, intravenously, in combination with hyperthermia and oncostatin; the combination of floretin and hyaluronic acid abruptly relieved pain.

Dr. Phok prescribed the patient probantine, which was used for pain caused by intestinal adhesion, which is usually removed by anticholinergics. Dr. Fok suggested that the patient be treated at home using 10 mg feldon (subcutaneous) and 500 mg naprosin suppositories once daily, and also using zantak (150 mg twice daily).

In addition to this treatment, dr. Fok prescribed vibramycin (doxycillin) 200 mg once daily and 100 mg daily for 14 days. It is an antibacterial agent that is also capable of blocking intracellular and anaerobic glycolysis.

Further Implications

A recent biopsy showed chronic inflammation of the lower third of the esophagus, and the tube was removed from the esophagus; but no malignancies were observed.

Case XXXIII

The patient was treated with chemotherapy, the majority of the tumor regressed but the patient did not follow the prescribed treatment regimen. Initially, treatment significantly affected the patient's condition; this was reflected in changes in liver function. Alkaline phosphatase was not increased. The patient felt general weakness, bruising, fatigue, and no appetite. This condition was ameliorated by the use of indomethacin with hyaluronic acid and treatment with deintoxicants.

The patient was examined and felt much better. Ultrasound showed that the tumor had practically regressed, accompanied by necrotic decay. Liver function returned to normal.

Case XXXIV

The patient had a chronic abscess and was located in the pelvis with colon obstruction.

January 5, an operation was performed. The cavity was rinsed and drained through the perineum. After a routine post-operative course, the patient was discharged from the hospital in 1990. January 13

But the patient had a rise in temperature because the patient had a large cavity in the pelvis and drainage was done by laparatomy through the lower abdomen. Laparatomy was performed two weeks before a visit to the doctor.

Dr. Fox looked around at the patient. According to dr. It takes 4-6 weeks for the focus to infect such a large area. Dr. Phok prescribed daily irrigation for 5 days with ampicillin, flagella and hyaluronic acid using 500 mg ampicillin and 500 mg flagilla. This is a much weaker treatment compared to Conventional Dr. Fock's treatments in that case.

After another examination, the abscess area was found to be engorged. The patient complained that on Saturday and Sunday med. the sisters had a hard time introducing the catheter. Dr '. Phok concluded that granular tissue had formed in the cavity and that it had occurred very quickly. With this in mind, it should be appreciated that with chronic abscesses in the cavity, it is desirable that the healing process be slower.

Therefore, dr. Fox advised the patient to contact her as soon as the temperature rose. The patient also complained of mild skin pruritus, apparently a reaction to chilling, so the doctor prescribed ointment treatment on the skin.

t

Case XXXV

The woman was injured by the 9th and 12th nerve, located laterally from the base of the skull. There was suspicion of dentoid metastasis. An RI scan was performed, which showed minor pathology in the area.

After being diagnosed with malignant neglected melanoma at a cancer research center in Ontario, the patient was discharged from the hospital as incurable.

Later, colleagues at the Cancer Center were surprised to learn about dr. The results of Fok's treatment. This treatment included hyperthermia and chemotherapy with hyaluronic acid. Conventional doses of carboplatin and low doses of methotrexate with hyaluronic acid were used.

The chest was clean, with some stable lesions in the kidney and liver, but these were well controlled. The language function normalized over the summer. But in the last three or four weeks, lesions have appeared.

After a recent neurological examination, it was found that. this function normalized to only lesions on the left side of the larynx, and slight fasciculation and atrophy of the left tongue were also observed.

The patient's condition was good.

Further results

Recently, a combination of hyaluronic acid (300 mg / day), NSPUP and vitamin C (50 mg / day) was administered to the patient. The tumors disappeared completely.

I

Case XXXVI

The patient underwent mesothelioma surgery and was treated with an adjuvant. It has been 7 years since the initial diagnosis. During the spring of this year, the patient had a relapse in Florida. While dr. He did three phoco biopsies and did not detect any tumor cells. Clinical examination with CT scan and liver ultrasound confirmed the diagnosis.

The patient was prescribed floretin treatment with hyaluronic acid .irhiperteri j a. Initially, there was no significant improvement. Thereafter, the patient did not undergo chemotherapy but used only floretin with very high doses of hyaluronic acid. The response to treatment was good, but fluids began to build up, which according to Dr. Focuses were formed when the tumor collapsed. Tumor decay was confirmed by ultrasound; the result of this cleavage was fluid formation at the tumor site.

The patient was treated for one day with hyperthermia and floretine hyaluronic acid. For detoxification, the patient received two days of vitanim C with hyaluronic acid. The patient was also given Lazix (furosemide, a diuretic) with hyaluronic acid.

The patient's creatinine level, which was initially 400 mM / L, decreased to 155 mM / Ι, respectively, from elevated to normal liver function. According to dr. Fok, the patient did not need further treatment because most of the tumor had regressed due to the patient's immune response, assisted by the introduction of hyaluronic acid, which is a mediator of drugs and antibodies.

1990 m. In July, ascites of moderate size and fluid in the body were detected. The patient was prescribed

TM _ furosemide (Lazix) and hyaluronic acid. Excessive urine excretion significantly improved the patient's condition.

Case XXXVII A woman of the year was diagnosed with: Stage III cervical carcinoma. She was treated with irradiation at a cancer center but was unsuccessful. The tumor continued to grow, which was recorded after approximately 1-2 treatments with irradiation. She was observed by dr. Yaldo St. At Mary's Hospital. It was given high doses of spirubicin, cisplatin, which did not cause tumor regression, which was determined by intravaginal examination and biopsy, on the contrary, the condition was worsened by pain with partial bladder obstruction, which was found in 1990. June March 28 abdominal CT scan.

The laparatomy revealed a large tumor with large areas of necrosis that covered the iliac artery and vein and was obturated, so the surgeon assessed the tumor as inoperable because the tumor was in the small and large pelvis. The patient was examined by a surgeon and urologists by ironcologists.

In the case of rectal obstruction, a colostomy was performed. Additionally, part of the rectum was used by surgeons to construct an artificial bladder.

The patient developed acute pain for several weeks before and after the operation. Administration of high doses of morphine intravenously resulted in only a slight reduction in pain '. July 8 a rise in temperature was recorded, and a CAT scan showed an abscess in the left pelvis. The abscess was drained during a CAT scan and the patient was systematically administered antibiotics to improve the condition.

I

Thereafter, this patient was treated by dr. Fock. He prescribed treatment with ampicillin, which was administered via a catheter, with hyaluronic acid (1 g ampicillin and 300 mg hyaluronic acid). In addition, the patient was intravenously administered 1 mg ampicillin and annef and flagilla systemically with 500mg of Life Core hyaluronic acid. The patient was also given 100 mg of indomethacin intravenously with 500 mg of hyaluronic acid (Life Core). After 12 hours, pain abruptly abated, symptoms of infection disappeared, drainage of abscess almost stopped. Her massive left leg, due to venous and lymph node obturation, returned to normal size within 12 hours.

The patient continued on the same course of treatment, which resulted in pain relief and improvement on June 18th. she was discharged from hospital without antibiotic treatment. Systemic analgesia with morphine was discontinued. The patient was not treated with hyperthermia and chemotherapy and / or oncostatin, floretin. She was treated with antioxidant therapy, combining with hyaluronic acid and administering indcmetacin and hyaluronic acid. The patient's condition improved dramatically, as evidenced by the combination of indomethacin and hyaluronic acid, providing targeted transport of the product to pathological tissue, improved macrophage function, enhanced immunity and tumor destruction.

Case XXXVIII

The patient was diagnosed with AIDS (HIV) and treated with indomethacin (NSPUP), vitamin C, interferon (DMSO) and / or hyaluronic acid, which resulted in an unexpected and sustained improvement in the patient's condition.

Case XXXIX

A patient with a backpack had back pain. Orally used analgesics, preparations for back rubbing, but the patient did not improve. After using NSPUP with hyaluronic acid, the pain of the hyaluronic acid sodium, which was applied externally to the patient's back, was reduced and then disappeared completely.

Side effects were observed with indomethacin dissolved in N-methylglucamine and naproxen dissolved in hyaluronic acid. But Toradol, in the form of (+/-) ketorac tromethamine salt, an inhibitor of prostaglandin biosynthesis and an anti-inflammatory, provides pain relief and no side effects.

The case of XL

The patient was diagnosed with AIDS and as a consequence of this disease, lung tumors were on the verge of death:

1.4x10³/ liter. The patient had methacin (300 mg), vitamin C (50 mg) daily, and hyaluronic acid, hyaluronic acid sodium (300 mg). After treatment, the leukocyte count was 8.2x10⁹/ liter, trpmbocytes - 63x10⁹/ liter. Lymphocyte count doubled.

The patient's leukocyte counts were administered intravenously before treatment. Additional animal studies were performed

In addition, animal studies (rats) have been conducted with the following results:

Increased antibiotic activity with hyaluronic acid. A model of chronic abscess in rats (rat Sprague dawley) was used. Bacterial pills were administered into the abdomen of each rat followed by treatment with the indicated regimen. In this model, the therapeutic activity of gentamicin was compared with that of gentamicin when used in combination with hyaluronic acid, and these studies clearly showed that the animal's improvement was more marked with the given combination than with the intravenous antibiotic. If antibiotic insensitivity is observed, it may be possible to administer the antibiotic in lower doses with hyaluronic acid. See. 1/1.

In another trial, implants from rat ACI strain (black) were transplanted into Lewis Strain rats (white), and the possibility of increasing implant survival time by administering a Lewis Strain combination of immunodepressants to hyaluronic acid (HA) in rats was investigated. Implant life depends to a large extent on the body's ability to suppress implant rejection, which can be stimulated by optimal immunodepressant activity, which is rarely achieved because an effective amount of depressant is out of the implant area. The combination of immunodepressants with hyaluronic acid can overcome these disadvantages. This can be accomplished by optimizing immunodepressant / implantant activity with specific agents and a combination of hyaluronic acid. A standard rat graft model was used for the studies. The immunodepressant cyclosporine was used. Research has shown that the use of hyaluronic acid significantly increases the life of the implant.

Lifetime of Implant Using Various Treatments (July 12, 1990)

<td colspan="2">Cy + HA #</td><td>Daily</td>

<td></td><td> 1</td><td> 20</td>

<td></td><td> 2</td><td> 19</td>

<td></td><td> 3</td><td> 1</td>

<td></td><td> 4</td><td> 20</td>

<td></td><td> 5</td><td> 19</td>

<td></td><td> 6</td><td> 20</td>

<td></td><td> 7</td><td> 20</td>

<td></td><td> 8</td><td> 20</td>

<td></td><td> 9</td><td> 20</td>

<td></td><td> 10</td><td> 19</td>

<td></td><td> 11</td><td> 19</td>

<td></td><td> 12</td><td> 20</td>

<td></td><td> 13</td><td> 21</td>

<td></td><td> 14</td><td> 19</td>

<td></td><td> 15</td><td> 19</td>

<td></td><td> 16</td><td> 20</td>

<td></td><td> 17</td><td> 20</td>

<td></td><td> 18</td><td> 20</td>

<td></td><td> 19</td><td> 20</td>

<td></td><td> 20</td><td> 19</td>

<td></td><td> 21</td><td> 17</td>

<td></td><td> 22</td><td> 14</td>

<td></td><td> 23</td><td> 14</td>

<td></td><td> 24</td><td> 14</td>

<td></td><td> 25</td><td> 19</td>

<td>Average</td><td> 17,917</td><td> 19,615</td>

<td>SE</td><td> 0,723</td><td> 0,213</td>

CyA + HA vs CyA = P size, one-sided

ANOVA = &lt;0.05 (= 0.0287) LSDMRT = &lt;0.05

CyA - Ciclosporin

HA - hyaluronic acid

The present invention may be practiced in other embodiments within the scope of the disclosure.